Renin Inhibition: A New Approach to Cardiovascular Therapy

Frishman, William H.; Fozailoff, Alan; Lin, Cherry; Dike, Chidiadi

doi:10.1002/j.1552-4604.1994.tb04000.x

Cited by 18 publications

(8 citation statements)

References 65 publications

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“…[3][4][5] Such a RAS functions to meet tissue specific needs 6 and is involved in the disease development of relevant tissues. [7][8][9][10] The angiotensinconverting enzyme gene (ACE) encodes a key enzyme in the RAS, which converts angiotensin I to the potent vasoconstrictor angiotensin II. 1,2,11 An insertion/deletion (I/D) polymorphism has been reported to be located in intron 16 of the ACE, and the angiotensin-converting enzyme (ACE) level is higher in subjects with D allele than those with I allele.…”

Section: Introductionmentioning

confidence: 99%

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and pancreatitis risk: A meta-analysis

Fang

Pan

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Objective: Many studies have focused on the relationship between the angiotensin-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism and pancreatitis risk, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between ACE I/D polymorphism and pancreatitis risk. Methods: Relevant publications were searched in several widely used databases and seven studies from six eligible articles were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between ACE I/D polymorphism and pancreatitis risk. Results: Significant associations between ACE I/D polymorphism and pancreatitis risk were observed in both overall meta-analysis for DI versus II (OR=0.80, 95% CI=0.67–0.96) and DD + DI versus II (OR=0.83, 95% CI=0.70–0.98), and acute pancreatitis subgroup for DI versus II (OR=0.65, 95% CI=0.44–0.95). However, no significant pancreatitis risk variation was detected for all genetic models in the subgroup meta-analysis based on ethnicity. Conclusions: According to the results of our meta-analysis, the ACE I/D polymorphism probably associates with pancreatitis risk, especially acute pancreatitis risk, with the I allele acting as a risk factor.

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Section: Introductionmentioning

confidence: 99%

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and pancreatitis risk: A meta-analysis

Fang

Pan

et al. 2014

J Renin Angiotensin Aldosterone Syst

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“…Despite the attractiveness of renin inhibition and the success of early compounds in validating it as therapeutic target, further drug development had been marred by issues of potency, bioavailability, duration of action and costs of synthesis. For instance, although potent, renin inhibitors such as remikiren and enalkiren showed poor oral bioavailability (29). Although this was improved somewhat with agents such as zankiren and terlakiren (29), further development of renin inhibitors was halted in the mid‐1990s, apparently for commercial reasons in the setting of the success of angiotensin receptor blocking agents.…”

Section: Development Of Renin Inhibitorsmentioning

confidence: 99%

Importance of renin in blood pressure regulation and therapeutic potential of renin inhibition

Ferro¹,

Gilbert²,

Krum³

2006

International Journal of Clinical Practice

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Despite improvements in its detection and treatment, hypertension remains a significant public health problem worldwide. In recent years, many international hypertension societies and organisations have set increasingly rigorous blood pressure (BP) targets, with the aim of reducing cardiovascular complications, and this has in turn necessitated the use of more antihypertensive medications to reach these targets in individual patients. There is therefore an ongoing need to develop antihypertensive drugs with new mechanisms of action. Renin inhibitors represent a novel class of compounds which offer considerable promise as BP-lowering agents. Here, we review the rationale for renin inhibition as a therapeutic target and examine the preclinical and clinical evidence for the antihypertensive effectiveness of the renin inhibitors.

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“…In addition to its release into the blood from the juxtaglomerular apparatus of the kidney, renin and other components of the RAS have been identified in a number of extrarenal tissues (Urata et al 1988;Cotter et al 1990;Troffa et al 1990) and plasma renin is known to be taken up by the vasculature (Swales and Samani 1990). Renin is the rate-limiting enzyme in the RAS cascade, and inhibition of this enzyme leads to decreased production of circulating and tissue angiotensins (e.g., angiotensins I, II, III, and IV) and consequently to a reduction in blood pressure (Frishman et al 1994). Enalkiren (A-72517), an example of a potent renin inhibitor, has been shown to lower blood pressure in animal models in which a portion of their blood pressure is dependent on the RAS (Kleinert et al 1992).…”

Section: Introductionmentioning

confidence: 97%

“…Major breakthroughs in this area include the development of angiotensin converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonists, which are both clinically used as general antihypertensive agents (Brunner et al 1994;Fouad-Tarazi 1994;Opie 1993;Pitt et al 1997;Hegner et al 1997;Lang et al 1997). Another target of the RAS cascade that continues to be actively investigated for possible therapeutic development in the treatment of hypertension is renin (Frishman et al 1994;Jauch et al 1996;Jones et al 1997;Sueirasdiaz et al 1997). In addition to its release into the blood from the juxtaglomerular apparatus of the kidney, renin and other components of the RAS have been identified in a number of extrarenal tissues (Urata et al 1988;Cotter et al 1990;Troffa et al 1990) and plasma renin is known to be taken up by the vasculature (Swales and Samani 1990).…”

Section: Introductionmentioning

confidence: 97%

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

Bolger¹,

Vigeant²,

Liard³

et al. 1999

Can. J. Physiol. Pharmacol.

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The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.

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Renin Inhibition: A New Approach to Cardiovascular Therapy

Cited by 18 publications

References 65 publications

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and pancreatitis risk: A meta-analysis

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and pancreatitis risk: A meta-analysis

Importance of renin in blood pressure regulation and therapeutic potential of renin inhibition

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

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